Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus.

The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system's response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia

Genomic insight into diet adaptation in the biological control agent Cryptolaemus montrouzieri

Background: The ladybird beetle Cryptolaemus montrouzieri Mulsant, 1853 (Coleoptera, Coccinellidae) is used worldwide as a biological control agent. It is a predator of various mealybug pests, but it also feeds on alternative prey and can be reared on artificial diets. Relatively little is known about the underlying genetic adaptations of its feeding habits. Results: We report the first high-quality genome sequence for C. montrouzieri. We found that the gene families encoding chemosensors and digestive and detoxifying enzymes among others were significantly expanded or contracted in C. montrouzieri in comparison to published genomes of other beetles. Comparisons of diet-specific larval development, survival and transcriptome profiling demonstrated that differentially expressed genes on unnatural diets as compared to natural prey were enriched in pathways of nutrient metabolism, indicating that the lower performance on the tested diets was caused by nutritional deficiencies. Remarkably, the C. montrouzieri genome also showed a significant expansion in an immune effector gene family. Some of the immune effector genes were dramatically downregulated when larvae were fed unnatural diets. Conclusion: We suggest that the evolution of genes related to chemosensing, digestion, and detoxification but also immunity might be associated with diet adaptation of an insect predator. These findings help explain why this predatory ladybird has become a successful biological control agent and will enable the optimization of its mass rearing and use in biological control programs

Serological Thymidine Kinase 1 is a Biomarker for Early Detection of Tumours—A Health Screening Study on 35,365 People, Using a Sensitive Chemiluminescent Dot Blot Assay

Serological thymidine kinase 1 (STK1) is a reliable proliferation marker for prognosis, monitoring tumour therapy, and relapse. Here we investigated the use of STK1 in health screening for early detection of pre-malignant and malignant diseases. The investigation was based on 35,365 participants in four independent health screening studies in China between 2005–2011. All participants were clinically examined. The concentration of STK1 was determined by a sensitive chemiluminescent dot blot ECL assay. The ROCvalue of the STK1 assay was 0.96. At a cut-off STK1 value of 2.0 pM, the likelihood (+) value was 236.5, and the sensitivity and the specificity were 0.78 and 0.99, respectively. The relative number of city-dwelling people with elevated STK1 values (≥2.0 pM) was 0.8% (198/26,484), while the corresponding value for the group of oil-field workers was 5.8% (514/8,355). The latter group expressed significantly higher frequency of refractory anaemia, fatty liver, and obesity, compared to the city dwellers, but no cases of breast hyperplasia or prostate hyperplasia. Furthermore, people working in oil drilling/oil transportation showed higher STK1 values and higher frequency of pre-malignancies and benign diseases than people working in the oil-field administration. In the STK1 elevated group of the city-dwelling people, a statistically significantly higher number of people were found to have malignancies, pre-malignancies of all types, moderate/severe type of hyperplasia of breast or prostate, or refractory anaemia, or to be at high risk for hepatitis B, compared to people with normal STK1 values (<2.0 pM). No malignancies were found in the normal STK1 group. In the elevated STK1 group 85.4% showed diseases linked to a higher risk for pre-/early cancerous progression, compared to 52.4% of those with normal STK1 values. Among participants with elevated STK1 values, 8.8% developed new malignancies or progress in their pre-malignancies within 5 to 72 months, compared to 0.2% among people with normal STK1 values. People who showed elevated STK1 values were at about three to five times higher risk to develop malignancies compared to a calculated risk based on a cancer incidence rate of 0.2–0.3%. We conclude that serological TK1 protein concentration is a reliable marker for risk assessment of pre/early cancerous progression

Luteolin Ameliorates Hypertensive Vascular Remodeling through Inhibiting the Proliferation and Migration of Vascular Smooth Muscle Cells

Objectives. Preliminary researches showed that luteolin was used to treat hypertension. However, it is still unclear whether luteolin has effect on the hypertensive complication such as vascular remodeling. The present study was designed to investigate the effect of luteolin on the hypertensive vascular remodeling and its molecular mechanism. Method and Results. We evaluated the effect of luteolin on aorta thickening of hypertension in spontaneous hypertensive rats (SHRs) and found that luteolin could significantly decrease the blood pressure and media thickness of aorta in vivo. Luteolin could inhibit angiotensin II- (Ang II-) induced proliferation and migration of vascular smooth muscle cells (VSMCs). Dichlorofluorescein diacetate (DCFH-DA) staining result showed that luteolin reduced Ang II-stimulated ROS production in VSMCs. Furthermore, western blot and gelatin zymography results showed that luteolin treatment leaded to a decrease in ERK1/2, p-ERK1/2, p-p38, MMP2, and proliferating cell nuclear antigen (PCNA) protein level. Conclusion. These data support that luteolin can ameliorate hypertensive vascular remodeling by inhibiting the proliferation and migration of Ang II-induced VSMCs. Its mechanism is mediated by the regulation of MAPK signaling pathway and the production of ROS

A simulation study on the measurement of D0-D0bar mixing parameter y at BES-III

We established a method on measuring the \dzdzb mixing parameter $y$ for BESIII experiment at the BEPCII $e^+e^-$ collider. In this method, the doubly tagged $\psi(3770) \to D^0 \overline{D^0}$ events, with one $D$ decays to CP-eigenstates and the other $D$ decays semileptonically, are used to reconstruct the signals. Since this analysis requires good $e/\pi$ separation, a likelihood approach, which combines the $dE/dx$, time of flight and the electromagnetic shower detectors information, is used for particle identification. We estimate the sensitivity of the measurement of $y$ to be 0.007 based on a $20fb^{-1}$ fully simulated MC sample.Comment: 6 pages, 7 figure

Pigment epithelium-derived factor protects retinal ganglion cells

BACKGROUND: Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors. RESULTS: Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC(50 )= 31 μM). In the presence of 100 μM glutamate, RGC number decreased to 55 ± 4% of control (mean ± SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 ± 4%, n = 60, P < 0.001). PEDF protected against both insults with EC(50 )values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor κB (NFκB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF. CONCLUSION: We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFκB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma

Health-related quality of life in glioma patients in China

<p>Abstract</p> <p>Background</p> <p>Health-related quality of life (HRQOL) has been increasingly emphasized in cancer patients. There are no reports comparing baseline HRQOL of different subgroups of glioma patients prior to surgery.</p> <p>Methods</p> <p>HRQOL assessments by the standard Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30, version 3.0), the Mini-Mental State Examination and Karnofsky Performance Status were obtained from glioma patients prior to surgery.</p> <p>Results</p> <p>Ninety-two pathologically confirmed glioma patients were recruited. There were 84.8% patients with emotional impairment, 75% with social and cognitive impairment, 70.7% with physical impairment, and 50% with role impairment. Eighty-two percent of patients reported fatigue symptoms, 72.8% reported pain, 50% reported appetite loss, 39.1% reported insomnia, and 36.9% reported nausea/vomiting, whereas other symptoms (dyspnea, diarrhea, constipation) in the QLQ-C30 were reported by fewer than 30% of patients. Fatigue and pain symptoms and all "functioning" scales were strongly correlated with global health status/quality of life (QoL). Fatigue was strongly related to all functioning scales, pain, appetite loss, and global health status/QoL. No difference in baseline HRQOL prior to surgery was reported between females and males, among different lesion locations, or between normal- and abnormal-cognition subgroups of glioma patients. Age, KPS, WHO grade, and tumor recurrence significantly affected HRQOL in glioma patients.</p> <p>Conclusions</p> <p>These data provided the baseline HRQOL in glioma patients prior to surgery in China. Most pre-surgery glioma patients indicated emotional, social, cognitive, physical, and role impairment. Fatigue, pain, appetite loss, insomnia, and nausea/vomiting were common in these patients. The fatigue and pain symptoms and all types of functioning strongly affected global health status/QoL. Old age, worse performance status, WHO grade IV and tumor recurrence had deleterious effects on HRQOL.</p

Comparison of intravascular ultrasound guided versus angiography guided drug eluting stent implantation: a systematic review and meta-analysis

BACKGROUND: Intravascular ultrasound (IVUS) can be a useful tool during drug-eluting stents (DES) implantation as it allows accurate assessment of lesion severity and optimal treatment planning. However, numerous reports have shown that IVUS guided percutaneous coronary intervention is not associated with improved clinical outcomes, especially in non-complex patients and lesions. METHODS: We searched the literature in Medline, the Cochrane Library, and other internet sources to identify studies that compare clinical outcomes between IVUS-guided and angiography-guided DES implantation. Random-effects model was used to assess treatment effect. RESULTS: Twenty eligible studies with a total of 29,068 patients were included in this meta-analysis. The use of IVUS was associated with significant reductions in major adverse cardiovascular events (MACE, odds ratios [OR] 0.77, 95 % confidence intervals [CI] 0.71-0.83, P < 0.001), death (OR 0.62, 95 % CI 0.54-0.71, p < 0.001), and stent thrombosis (OR 0.59, 95 % CI: 0.47-0.73, P < 0.001). The benefit was also seen in the repeated analysis of matched and randomized studies. In stratified analysis, IVUS guidance appeared to be beneficial not only in patients with complex lesions or acute coronary syndromes (ACS) but also patients with mixed lesions or presentations (MACE: OR 0.69, 95 % CI: 0.60-0.79, p < 0.001, OR 0.81, 95 % CI 0.74-0.90, p < 0.001, respectively). By employing meta-regression analysis, the benefit of IVUS is significantly pronounced in patients with complex lesions or ACS with respect to death (p = 0.048). CONCLUSIONS: IVUS guidance was associated with improved clinical outcomes, especially in patients with complex lesions admitted with ACS. Large, randomized clinical trials are warranted to identify populations and lesion characteristics where IVUS guidance would be associated with better outcomes